Targets, Structures and Drugs (TSD) Research Program Project Summary The mission of the newly formed Targets, Structures, and Drugs (TSD) Program is to accelerate the development of novel therapies for cancer treatment through a pipeline that identifies lead compounds or macromolecular target structures, and progresses their development by medicinal chemistry lead optimization, rational design, and preclinical evaluation using animal models, including naturally occurring canine models that are highly reflective of human disease. Purdue Center for Cancer Research (PCCR) academic leadership in drug discovery is characterized by development of novel inhibitors for targets validated by PCCR scientists. TSD's 50 Program members have shepherded 11 PCCR compounds into human clinical trials and 37 compounds (up from 24 at the last review) into preclinical evaluation, including a total of 22 canine studies of PCCR leads and novel technologies. Our goal the next grant cycle is to further enhance drug development by continuing to enhance therapeutic lead development. The TSD is led by three co-leaders: David Thompson (Lead, Medicinal Chemistry cluster), Deborah Knapp (Lead, Target Validation cluster), and John Tesmer (Lead, Chemical and Structure Biology cluster). The TSD developmental pipeline is further strengthened by the strategic addition of 24 new members since the last review, giving the TSD Program robust coverage in each phase of the drug development pipeline. Members of the TSD Program are active participants in the NCI Experimental Therapeutics ? Chemical Biology Consortium (Thompson, Director), NCI Comparative Oncology Clinical Trials Consortium (Childress, Purdue Director), DARPA Make It (Thompson, co- Director), as well as NIH T32 Training Grants in Molecular Biophysics - (Tesmer, Director) and Drug Discovery (Dai, co-Director). Over this last funding period, TSD faculty have secured $9.7 million in peer-reviewed cancer- related support; have published 505 peer-reviewed articles, (25 % high-impact) with 14% intra-programmatic and 15% inter-programmatic collaborations (49% inter-institutional). Further, TSD faculty translate their research into deliverables, including 53 patents and 5 companies during this latest funding period. To facilitate our goals of advancing PCCR lead compounds, the TSD program plans to: (1) strategically deploy programmatic funds to nucleate and support new inter- and intra-programmatic collaborations; (2) leverage Purdue's strength in cryo-electron microcopy (cryo-EM) to enhance structure-based drug design and target validation; (3) further develop scalable automated continuous synthesis of PCCR leads enabled by Boilermaker Health Innovations (BHI); (4) expand lead testing in canine spontaneous cancer models; and (5) inspire the continuing development of scientific leaders in cancer research through innovative training. We will further these goals by recruiting leading scientists, particularly in the areas of drug discovery, chemical biology, and cryo-EM and continue cultivating a transdisciplinary culture through TSD Program gatherings and by hosting targeted symposia of interest to our faculty.